Anasarca Secondary to Protein-Losing Enteropathy Leading to the Diagnosis of a Gastrointestinal Neuroendocrine Tumor in a Young Female: A Case Report From an Indian Suburb

A 34-year-old woman presented with worsening generalized swelling and breathlessness for four months; physical examination showed pallor, diffuse anasarca, and bilateral crackles on respiratory auscultation. Laboratory investigations showed severe hypoproteinemia, fat malabsorption with fat-soluble vitamin deficiency, and significant protein loss in the stool. Imaging studies revealed pulmonary edema, ascites, bowel wall edema, and a duodenal polyp. Further evaluating the duodenal polyp, a grade two duodenal neuroendocrine tumor (NET) was identified. She was managed with subcutaneous octreotide and duodenal polypectomy, resulting in significant clinical improvement. This case highlights the importance of diagnosing and managing protein-losing enteropathy secondary to gastric neuroendocrine tumors.


Introduction
Gastrointestinal neuroendocrine tumors (GNETs) are uncommon neoplasms, with an annual incidence ranging from one to two cases per 200,000 individuals.These tumors originate from neuroendocrine cells distributed throughout the gastrointestinal (GI) tract.Clinical manifestations vary depending on their location and hormone secretion profile.One less common but clinically significant presentation of GNETs is protein-losing enteropathy (PLE) [1].PLE is the excessive loss of plasma proteins into the GI tract, leading to hypoproteinemia and subsequent edema.The pathophysiology of PLE in the context of GNETs involves mechanisms such as mucosal disruption, inflammation, or lymphangiectasia, which impair normal protein absorption and retention in the body [2].Diagnostic workup often involves imaging modalities, endoscopic evaluation, and histopathological confirmation.Management strategies aim to control tumor growth, alleviate symptoms, and address nutritional deficiencies [2].This case study explores the clinical features, diagnostic challenges, and current management strategies of PLE secondary to GNETs.

Case Presentation
A 34-year-old woman presented to the casualty department complaining of swelling all over her body and difficulty breathing.She was asymptomatic four months ago, then she noticed swelling in both legs, which progressively worsened to involve her entire body.In the past week, she was breathless at rest, which was not associated with chest pain or palpitations.Before the past week, she never had sleep disturbances secondary to breathlessness.There was no history of fever, weight loss, or decreased appetite.There were also no complaints of abdominal pain, nausea, vomiting, blood in stools, bowel, or bladder disturbances.She had no significant medical, family, or obstetric history.
On examination, she was found to have pallor and diffuse anasarca.There were no signs of icterus, cyanosis, clubbing, or lymphadenopathy.Her blood pressure was 100/60 mmHg, pulse rate was 112 beats per minute, oxygen saturation was 95% on four liters of oxygen, and respiratory rate was 30 breaths per minute.
Abdominal examination showed tense ascites without dilated veins or organomegaly.Respiratory system examination revealed bilateral crackles.The cardiovascular examination was normal, with no murmurs or added heart sounds, and the nervous system examination was within normal limits.
Initially, acute liver injury, acute kidney injury, or nephrotic syndrome was suspected.However, investigations revealed anemia due to deficiencies in iron and vitamin B12.Further examination uncovered protein deficiency, as well as deficiencies in calcium and vitamin D. Abnormalities in activated partial thromboplastin time (aPTT) and prothrombin time (PTINR) indicated a clotting factor deficiency associated

TABLE 2: Additional investigation and its interpretation
2D-ECHO showed a normal left ventricular function (60%), no wall motion abnormality, and normal valvular function with mild pericardial effusion (non-tapable) (Video 1).

VIDEO 1: 2D echocardiography of heart (parasternal short axis view) showing normal left ventricular function with a thin rim of pericardial effusion
View video here: https://youtu.be/wgoqCl7kCQQ USG of the abdomen and pelvis revealed grade one fatty liver, normal kidney size, normal spleen, and moderate to gross ascites on presentation (Figure 1).

FIGURE 1: USG of the patient after paracentesis
A: normal spleen; B (black arrow) and C (white arrow) show ascitic pockets HRCT thorax showed diffuse ground-glass opacity over the anterior segment, posterolateral segments of the left lower lobe, and anteromedial segment of the right lower lobe of the lung, suggestive of pulmonary edema.Bilateral pleural effusion was noted (Figure 2).CECT of the abdomen and pelvis showed fatty liver, mild mucosal thickening in the bowel wall, normal kidney size, diffuse subcutaneous edema of the abdominal wall (anasarca), and gross ascites (Figure 3).

FIGURE 3: Black arrow showing ascites in the CECT of the abdomen
On day five, the patient's clinical status remained the same.Laboratory investigations showed no proteinuria, stool examination was normal (no fat globules), and 24-hour fecal alpha-1 antitrypsin (A1AT) levels indicated protein loss in the stool as shown in Table 3.The autoimmune panel and ANA profile were negative (Table 4).An upper GI endoscopy revealed edematous stomach mucosa and two duodenal polyps measuring approximately 1 to 2 cm in size, with no ulcers or erosions observed (Figure 4).Deep enteroscopy showed edematous jejunal mucosa.The colonoscopy study indicated nodularity in the terminal ileum and edema from the cecum to the rectal mucosa.Fibroscan showed no evidence of liver fibrosis, and both the portal vein doppler and hepatic vein doppler studies were normal.

FIGURE 4: Upper GI endoscopy image
The black arrow shows duodenal polyps.

GI, gastrointestinal
CECT enterography shows mucosal thickening in the duodenum, jejunum, and stomach; the rest of the bowel appears normal in thickness (Figure 5).Immunohistochemistry (IHC) markers showed synaptophysin cytoplasmic positivity, chromogranin positivity, and a Ki-67 index of 6-8%.Grade two neuroendocrine tumor (NET) of the duodenum was concluded (Figure 6 and Figure 7).MEN syndrome workup and Ga-DOTATATE PET/CT were advised, but the patient declined further investigation due to financial constraints.
She was started on subcutaneous octreotide injections for long-term maintenance therapy, and a duodenal polypectomy was performed.After a few weeks, the patient showed significant improvement, and both anasarca and malabsorption resolved (Table 5).

Discussion
Protein-losing enteropathy PLE manifests as a symptom rather than a definitive diagnosis.Any patients presenting with low protein levels must be evaluated thoroughly for common causes like chronic liver diseases, severe malnutrition, and nephrotic syndrome before considering PLE.The protein loss in PLE occurs irrespective of the size of the protein molecule, leading to decreased serum levels of both albumin and globulins [3,4].

Pathophysiology
PLE arises when GI loss of protein exceeds the body's ability to compensate.The underlying causes can vary; important ones are discussed below in Table 6.

Conditions
A breach in the mucosal membrane causes malabsorption and protein loss Infective etiologies such as gastroenteritis, ulcerative or erosive lesions in the stomach and duodenum, Zollinger-Ellison syndrome, and pseudomembranous colitis [3,4,5].
Increased hydrostatic pressure or lymphatic obstruction of the splanchnic circulation Right heart failure, Fontan procedure, heart failure with congestion, cirrhosis with portal hypertension, Budd-Chiari syndrome, lymphoma, mesenteric tuberculosis, and lymphangiectasia [3,7].
Mechanisms by which neoplasia causes PLE: It can be due to direct mass effect, increased peristalsis, decreased surface area of absorption, mucosal and submucosal inflammation, or as part of a paraneoplastic syndrome.

Diagnosis
Diagnosing PLE requires extensive evaluation to identify the underlying cause.Laboratory tests, imaging studies, and endoscopic procedures are essential in guiding the diagnostic process.A crucial diagnostic step is demonstrating elevated fecal loss of A1AT [3,8].
A1AT clearance=(volume of the stool)×(stool A1AT)/(serum A1AT) An elevated A1AT clearance (>27 mL/day) suggests GI protein loss, with approximately 80% sensitivity.Spot stool A1AT tests are less sensitive, while random stool A1AT levels with serum A1AT are practical for monitoring PLE treatment.When A1AT clearance is inconclusive, technetium 99m-labeled human serum albumin (HSA) scintigraphy can provide further diagnostic insights [8].Imaging studies like CT or MRI may help in identifying the underlying cause, such as lymphatic obstruction or tumors.

Treatment
Treating the underlying cause is crucial.A protein-rich diet (2-3g/kg/day) is recommended, along with nutritional supplements to ensure adequate electrolytes, micronutrients, and vitamins.Regular monitoring of A1AT clearance or spot stool A1AT levels after initiating the treatment is recommended [3,4,6].

Gastric neuroendocrine tumors
GNETs are generally rare tumors; in the United States, the annual incidence is one to two cases per 200,000 people.These tumors originate from neuroendocrine cells of the pancreas, GI tract, and lungs and less commonly in the breast, prostate, thymus, and skin.They can manifest as well-differentiated tumors or they can progress to carcinomas, which are poorly differentiated [9].
Clinical presentation may vary from hormone-related symptoms from the tumor (functional NETs) or due to mass effect and metastasis.Common symptoms include flushing, diarrhea, abdominal pain, and symptoms of obstruction or bleeding [9,10].
Neuroendocrine cells produce functional hormones like serotonin, insulin, glucagon, and gastrin, depending on the specific subtype of the tumor.GNETs produce different hormones based on their cell of origin.For instance, duodenal NETs can present as gastrinomas, somatostatinomas, or paragangliomas.Gastrinomas are often associated with conditions like Zollinger-Ellison syndrome and multiple endocrine neoplasia (MEN 1) [9,10,11].Hormones and tumor markers of GNETs are mentioned in Table 7.
Histopathology: The NTE cells have oval nuclei with granular chromatin.Grading and differentiation determine the aggressiveness of the tumor.Two important features that decide the proliferation index of the cancer are the Ki67 index (a protein produced in large amounts during cell proliferation) and mitosis per 10 hpf (high power field) [11,12].WHO classification of GNETs is enumerated in Table 8.

TABLE 8: Histopathological features and grading of NETs
The 2022 WHO classification of gastric neuroendocrine tumors and NEC [12].
NETs, neuroendocrine tumors; NEC, neuroendocrine carcinoma Imaging: For suspected NET, it is recommended to undergo MRI or CT screening.CT of the chest, abdomen, and pelvis aids in tumor staging.Somatostatin analogs such as radio-isotope indium (In)-octreotide offer higher sensitivity for well-differentiated tumors [11,13,14].
Gallium-DOTATATE-PET/CT is the gold standard for diagnosing and staging NET [13].Endoscopy and colonoscopy are crucial for visualizing tumors and obtaining biopsies.Endoscopic ultrasound is the most

FIGURE 2 :
FIGURE 2: Bilateral pleural effusion (black arrow) and pulmonary edema (white arrow) noted in the HRCT of thorax

FIGURE 6 :FIGURE 7 :
FIGURE 6: The black arrow mark shows oval tumor cells tumor with significant mitotic activity or high Ki67 index.>20 >20 Median survival is approximately 1 yearSmall cell NECHighly aggressive neuroendocrine carcinoma with small cell morphology and very high mitotic activity.>20 Often >70 Generally poor prognosisLarge cell NECHighly aggressive neuroendocrine carcinoma with large cell morphology and very high mitotic activity.>20 Often >70 Generally poor prognosis The relevant lab values are presented in Table1 and Table 2.
with vitamin K deficiency.Additionally, fat malabsorption and resultant fat-soluble vitamin deficiencies were noted.Normal urine examination and normal liver function tests excluded the initial suspicions of liver or kidney dysfunction.

TABLE 5 : Comparison of the lab investigations on admission and the day of discharge
aPTT, activated partial thromboplastin time; PT, prothrombin time; NR, international normalized ratio; HDL, high-density lipoprotein; LDL, low-density lipoprotein